N-glucuronidation of the platelet-derived growth factor receptor tyrosine kinase inhibitor 6,7-(dimethoxy-2,4-dihydroindeno[1,2-C]pyrazol-3-yl)-(3-fluoro-phenyl)-amine by human UDP-glucuronosyltransferases.

The potential cancer therapeutic agent, 6,7-(dimethoxy-2, 4-dihydroindeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (JNJ-10198409), formed three N-glucuronides that were positively identified by liquid chromatography-tandem mass spectrometry and NMR as N-amine-glucuronide (Glu-A), 1-N-pyrazole-glucuronide (Glu-B), and 2-N-pyrazole-glucuronide (Glu-C). All three N-glucuronides were detected in rat liver microsomes, whereas only Glu-A and -B were found in monkey and human liver microsomes. In contrast to common glucuronides, Glu-B was completely resistant to beta-glucuronidase.

Contact rates and exposure to inter-species disease transmission in mountain ungulates.

The risk for a pathogen to cross the species barrier depends on the rate of efficient contacts between the species. However, contact rates between species have rarely been estimated from observations. Here we estimate contact rates and exposure of chamois Rupicapra rupicapra and Alpine ibex Capra ibex exposed to domestic pasteurellosis and brucellosis carried by sheep or cattle herds summering in mountain pastures.

Single amino acid substitution in the PC1/3 propeptide can induce significant modifications of its inhibitory profile toward its cognate enzyme.

The proprotein convertase PC1/3 is synthesized as a large precursor that undergoes proteolytic processing of the signal peptide, the propeptide and ultimately the COOH-terminal tail, to generate the mature form. The propeptide is essential for protease folding, and, although cleaved by an autocatalytic process, it remains associated with the mature form acting as an auto-inhibitor of PC1/3. To further assess the role of certain residues in its interaction with its cognate enzyme, we performed an alanine scan on two PC1/3 propeptide potential cleavable sites ((50)RRSRR(54) and (61)KR(62)) and an acidic region (65)DDD(67) conserved among species.

Choroidal amelanotic melanoma in a patient with oculocutaneous albinism.

Case Report: We describe the clinical presentation of a choroidal amelanotic melanoma in a 46-year-old woman with oculocutaneous albinism. Clinical aspects, investigations, and management are presented, and findings from computed tomography and magnetic resonance imaging are described. Microscopic findings and histopathological features, demonstrating a spindle B-cell melanoma of the choroid, are also reviewed.

Determination of kinetic law for toxic metals release during thermal treatment of model waste in a fluid-bed reactor.

Accumulation of toxic metals generated by thermal treatment of municipal solid waste presents a serious threat to the environment. A study was carried out to investigate the kinetic law of toxic metal release from municipal solid waste during their thermal treatment. Both direct and inverse models were developed in transient conditions.

Distortion management in slow-light pulse delay.

We describe a methodology to maximize slow-light pulse delay subject to a constraint on the allowable pulse distortion. We show that optimizing over a larger number of physical variables can increase the distortion-constrained delay. We demonstrate these concepts by comparing the optimum slow-light pulse delay achievable using a single Lorentzian gain line with that achievable using a pair of closely-spaced gain lines.

Metabolism and excretion of the antiepileptic/antimigraine drug, Topiramate in animals and humans.

The metabolism and excretion of 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate (TOPAMAX, topiramate, TPM) have been investigated in animals and humans. Radiolabeled [14C] TPM was orally administered to mice, rats, rabbits, dogs and humans. Plasma, urine and fecal samples were collected and analyzed.

Detection of a newly described pestivirus of Pyrenean chamois (Rupicapra pyrenaica pyrenaica) in France.

A pestivirus was detected and characterized in chamois (Rupicapra pyrenaica pyrenaica) originating from the French part of the Pyrenees. Phylogenetic analysis of the pestivirus was done on the basis of a fragment from the 5' noncoding region including 22 published nucleotide sequences of different pestivirus strains. Our strain was grouped within the clade of border disease viruses (BDV).

Prenatal diagnosis of Beckwith-Wiedemann syndrome.

Objectives: The diagnosis of Beckwith-Wiedemann syndrome (BWS) typically is made after birth. To our knowledge, no established guidelines exist for the prenatal diagnosis of this condition. We present two new cases of prenatally diagnosed BWS and propose a diagnostic schema.

The synthesis and evaluation of 10- and 12-membered ring benzofused enediyne amino acids.

The enediyne moiety is a versatile functional group found in natural anticancer and anti-infective agents, undergoing the Bergman cyclization reaction to afford a diradical which cleaves double-stranded DNA. We have incorporated the enediyne group into 10- (4-10) and 12-membered ring (11) cyclic amino acids and dipeptides, respectively, and explored their relative reactivity toward cyclization, varying N-substitution in the case of the 10-membered ring substrate, which gave the expected cyclization products in good yields when using either thermal conditions in the presence or absence of microwave irradiation. The N-tosyl substituted derivative (4) was shown to nick double-stranded supercoiled DNA.

Structure of non-(1-84) PTH fragments secreted by parathyroid glands in primary and secondary hyperparathyroidism.

Background: Non-(1-84) parathyroid hormone (PTH) fragments are large circulating carboxyl-terminal (C) fragments with a partially preserved amino-terminal (N) structure. hPTH (7-84), a synthetic surrogate, has been demonstrated to exert biologic effects in vivo and in vitro which are opposite to those of hPTH (1-34) on the PTH/PTHrP type I receptor through a C-PTH receptor. We wanted to determine the N structure of non-(1-84) PTH fragments.

Toward a scientifically rigorous basis for developing mapped ecological regions.

Despite the wide use of ecological regions in conservation and resource-management evaluations and assessments, a commonly accepted theoretical basis for ecological regionalization does not exist. This fact, along with the paucity of focus on ecological regionalization by professional associations, journals, and faculties, has inhibited the advancement of a broadly acceptable scientific basis for the development, use, and verification of ecological regions. The central contention of this article is that ecological regions should improve our understanding of geographic and ecological phenomena associated with biotic and abiotic processes occurring in individual regions and also of processes characteristic of interactions and dependencies among multiple regions.

Restitution in mapping models with an arbitrary amount of memory.

Restitution, the characteristic shortening of action potential duration (APD) with increased heart rate, has been studied extensively because of its purported link to the onset of fibrillation. Restitution is often represented in the form of mapping models where APD is a function of previous diastolic intervals (DIs) and/or APDs, A(n+1)=F(D(n),A(n),D(n-1),A(n-1),..

Palladium-catalyzed regioselective arylation of imidazo[1,2-b][1,2,4]triazine: synthesis of an alpha 2/3-selective GABA agonist.

A convergent, practical, and efficient synthesis of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (1), an orally active GABA(A) alpha(2/3)-selective agonist, is described. The seven-step, chromatography-free synthesis was demonstrated on a multi-kilogram scale and utilized biaryl bromide 6 and imidazotriazine 22 as key intermediates. Biaryl bromide 6 was prepared via a highly selective aromatic bromination.

Development of an inverse method to identify the kinetics of heavy metal release during waste incineration in fluidized bed.

This paper deals with the emission of heavy metals (HM) during the incineration of municipal solid waste in a fluidized bed reactor. This study focused on the development of a general method to identify the kinetics of vaporization of heavy metals from the on-line analysis of exhaust gas. This method is an inverse method, which requires only the time evolution of the HM concentration in exhaust gases (experimental data) and a global bubbling bed model developed for transient conditions at the reactor scale.

Tunable all-optical delays via Brillouin slow light in an optical fiber.

We demonstrate a technique for generating tunable all-optical delays in room temperature single-mode optical fibers at telecommunication wavelengths using the stimulated Brillouin scattering process. This technique makes use of the rapid variation of the refractive index that occurs in the vicinity of the Brillouin gain feature. The wavelength at which the induced delay occurs is broadly tunable by controlling the wavelength of the laser pumping the process, and the magnitude of the delay can be tuned continuously by as much as 25 ns by adjusting the intensity of the pump field.

All-optical switching in rubidium vapor.

We report on an all-optical switch that operates at low light levels. It consists of laser beams counterpropagating through a warm rubidium vapor that induce an off-axis optical pattern. A switching laser beam causes this pattern to rotate even when the power in the switching beam is much lower than the power in the pattern.

Safety and efficacy of intravitreal injection of ranibizumab in combination with verteporfin PDT on experimental choroidal neovascularization in the monkey.

Objective: To study the safety and efficacy of intravitreal injections of anti-vascular endothelial growth factor antibody fragment (ranibizumab [formerly known as rhuFabV2], Lucentis; Genentech, South San Francisco, Calif) in combination with intravenous verteporfin (Visudyne; Novartis, East Hanover, NJ) photodynamic therapy (PDT) on experimental choroidal neovascularization in the monkey eye.

Methods: Choroidal neovascularization was induced by laser injury in both eyes of cynomolgus monkeys and followed with weekly fundus photography and fluorescein angiography. Two weeks after induction, weekly treatments were initiated.

Trimethylsilyl-directed 1,3-dipolar cycloaddition reactions in the solid-phase synthesis of 1,2,3-triazoles.

[reaction: see text] A regioselective method for the preparation of 1,5-trisubstituted 1H-1,2,3-triazoles via a 1,3-dipolar cycloaddition of 1-trimethylsilylacetylenes with organoazides is described. Immobilization of the azide on REM resin and subsequent cycloaddition afforded a 2 x 2 x 4 x 3 membered 1,5-disubstituted 1H-1,2,3-triazole library with an average purified yield of 68%.

Photodynamic therapy in young patients with choroidal neovascularization following traumatic choroidal rupture.

Purpose: To assesses the role of photodynamic therapy (PDT) with verteporfin in young patients with choroidal neovascularization (CNV) secondary to traumatic choroidal rupture.

Design: Retrospective case series.

Methods: Of 26 eyes with traumatic choroidal rupture followed since 1984 at the retina service of university hospitals, all eyes diagnosed with CNV and treated with PDT were included.

Fast causal information transmission in a medium with a slow group velocity.

It is widely believed that the velocity of information upsiloni encoded on an optical pulse is equal to the group velocity upsilong, at least when upsilong is less than the speed of light in vacuum c. On the other hand, several authors suggest that upsiloni=c, although the size of the signal traveling at this velocity may be small, thereby making it difficult to measure. Here, we measure upsiloni for pulses propagating through a resonant "slow-light" medium where upsilong approximately 0.

An efficient chemoenzymatic approach to (S)-gamma-fluoroleucine ethyl ester.

[reaction: see text] An asymmetric synthesis of (S)-gamma-fluoroleucine ethyl ester 1 is described. The key transformation involves a lipase-catalyzed dynamic ring-opening of 2-(3-butenyl)azlactone 7b with EtOH to give amide ester (S)-6b in 84% enantiomeric excess. Removal of the N-pentenoyl group with N,N'-dibromodimethylhydantoin in the presence of trifluoroacetic acid afforded the titled compound, which was isolated as its hydrogen sulfate salt in 75% yield and >97% ee.

Synthesis of macrocycles via cobalt-mediated [2 + 2 + 2] cycloadditions.

We investigated the formation of macrocycles from alpha,omega-diynes in cobalt-mediated co-cyclotrimerization reactions. Long-chain alpha,omega-diynes underwent metal-mediated [2 + 2 + 2] cycloadditions with nitriles, cyanamides, or isocyanates in the presence of CpCo(CO)2 (Cp = cyclopentadienide) to yield pyridine-containing macrocycles, i.e.

Monoclonal antibody analysis of Perkinsus marinus extracellular products.

The protozoan oyster parasite Perkinsus marinus releases a complex set of extracellular products (ECP) during in vitro culture. These products have been previously implicated in parasite virulence, and their expression can be altered by medium supplementation with oyster tissue homogenate. Little is known regarding ECP function, regulation, or mechanism of storage and release.

Simultaneous analysis of citalopram and desmethylcitalopram by liquid chromatography with fluorescence detection after solid-phase extraction.

Objectives: To develop a HPLC method for the determination of citalopram (CIT) and desmethylcitalopram (DCIT).

Methods: Solid-phase extraction followed by fluorescence detection was used to measure CIT and DCIT in deproteinized plasma.

Results: The extraction recovery for both analytes was 104 +/- 3%.